A multifunctional metal-organic framework nanosystem disrupts redox homeostasis for synergistic therapy.

Synergistic therapies of photodynamic therapy (PDT) and chemodynamic therapy (CDT) via metal-organic frameworks (MOF) for cancer treatment have recently attracted a lot of attentions because of the limitations of insufficient reactive oxygen species (ROS) in single-modality approaches. However, few studies explored on the use of increased ROS synergized with chemotherapy (CT) to address the issue of inadequate anti-tumor efficacy in single-modality regimens. Here, the desired cascade nanoplatforms (noted as MOF(Cu)@Dox-PL NPs) were fabricated by a solvothermal method using tetrakis (4-carboxyphenyl) porphyrin (TCPP) and zirconyl(di)chloride octahydrate (ZrOCl2·8H2O) as raw material, followed by Cu2+ introduced into the porphyrin ring and doxorubicin (DOX) loaded into the nanoframework. In addition, the nanoparticles (NPs) were electrostatically and hydrophobically coated with phospholipid (PL) to improve the biocompatibility of the nanosystems. Singlet oxygen (1O2) was created by the MOF(Cu)@Dox-PL NPs to disturb intracellular redox equilibrium. The acidic microenvironment in cancer cells may cause the prior release of DOX, which encourages the production of hydrogen peroxide (H2O2). And the doped Cu2+ could deplete overexpressed reduced glutathione (GSH) to produce hydroxyl radicals (·OH) by catalyzing H2O2, further causing redox dyshomeostasis. In vivo experiments revealed that MOF(Cu)@Dox-PL nanosystem possessed good biosafety and a compelling therapeutic effect in 4T1 tumor-bearing mice. As a novel nanosystem, MOF(Cu)@Dox-PL NPs showed great potential in synergistic therapy based on redox dyshomeostasis for improving anti-tumor efficacy with high specificity.

Prussian Blue-Derived Nanoplatform for In Situ Amplified Photothermal/Chemodynamic/Starvation Therapy.

Chemodynamic therapy (CDT) is an emerging tumor treatment; however, it is hindered by insufficient endogenous hydrogen peroxide (H2O2) and high glutathione (GSH) concentrations in the tumor microenvironment (TME). Furthermore, CDT has limited therapeutic efficacy as a monotherapy. To overcome these limitations, in this study, a nanoplatform is designed and constructed from Cu-doped mesoporous Prussian blue (CMPB)-encapsulated glucose oxidase (GOx) with a coating of hyaluronic acid (HA) modified with a nitric oxide donor (HN). In the proposed GOx@CMPB-HN nanoparticles, the dopant Cu2+ ions are crucial to combining and mutually promoting multiple therapeutic approaches, namely, CDT, photothermal therapy (PTT), and starvation therapy. The dopant Cu2+ ions in CMPB protect against reactive oxygen species to deplete the intracellular GSH in the TME. Additionally, the byproduct Cu+ ions act as a substrate for a Fenton-like reaction that activates CDT. Moreover, H2O2, which is another important substrate, is produced in large quantities through intracellular glucose depletion caused by the nanoparticle-loaded GOx, and the gluconic acid produced in this reaction further enhances the TME acidity and creates a better catalytic environment for CDT. In addition, Cu2+ doping greatly improves the mesoporous Prussian blue (MPB) photothermal conversion performance, and the resultant increase in temperature accelerates CDT catalysis. Finally, the HN coating enables the nanoparticles to actively target CD44 receptors in cancer cells and also enhances vascular permeability. Therefore, this coating has multiple effects, such as facilitating enhanced permeability and retention and deep laser penetration. In vitro and in vivo experiments demonstrate that the proposed GOx@CMPB-HN nanoplatform significantly inhibits tumor growth with the help of in situ enhanced synergistic therapies based on the properties of the TME. The developed nanoplatform has the potential to be applied to cancer treatment and introduces new avenues for tumor treatment research.

Combination of photosensitizer and immune checkpoint inhibitors for improving the efficacy of tumor immunotherapy.

As a new type of antitumor strategy, the combined application of photodynamic therapy and immunotherapy will be a breakthrough in the field of tumor therapy. In this study, PD-L1McAb&HMME@Clip is used as the carrier to improve the low tumor response rate of immune checkpoint inhibitors. Firstly, by passive targeting technology, the carrier is delivered to the tumor site to increase the local drug concentration. Then, by photodynamic technology, HMME can produce large amount of reactive oxygen species and directly kill the tumor cells. Meanwhile, the tumor cell lysate with strong immunogenicity can promote the phagocytosis of dendritic cells and the activation of initial T cells. Finally, by immune technology, the PD-1/PD-L1 pathway is blocked in the tumor microenvironment, the killing ability of T cells to tumor cells can be restored, and the tumor recurrence and metastasis can be effectively inhibited by the autoimmune system, so as to achieve the goal of tumor treatment. Furthermore, we also highlight the potential benefits of immunotherapy as a surgical adjuvant therapy.

NIR Stimulus-Responsive PdPt Bimetallic Nanoparticles for Drug Delivery and Chemo-Photothermal Therapy.

The combination of chemotherapy and phototherapy has attracted increasing attention for cancer treatment in recent years. In the current study, porous PdPt bimetallic nanoparticles (NPs) were synthesized and used as delivery carriers for the anti-cancer drug doxorubicin (DOX). DOX@PdPt NPs were modified with thiol functionalized hyaluronic acid (HA-SH) to generate DOX@PdPt@HA NPs with an average size of 105.2 ± 6.7 nm. Characterization and in vivo and in vitro assessment of anti-tumor effects of DOX@PdPt@HA NPs were further performed. The prepared DOX@PdPt@HA NPs presented a high photothermal conversion efficiency of 49.1% under the irradiation of a single 808 nm near-infrared (NIR) laser. Moreover, NIR laser irradiation-induced photothermal effect triggered the release of DOX from DOX@PdPt@HA NPs. The combined chemo-photothermal treatment of NIR-irradiated DOX@PdPt@HA NPs exerted a stronger inhibitory effect on cell viability than that of DOX or NIR-irradiated PdPt@HA NPs in mouse mammary carcinoma 4T1 cells in vitro. Further, the in vivo combination therapy, which used NIR-irradiated DOX@PdPt@HA NPs in a mouse tumor model established by subcutaneous inoculation of 4T1 cells, was demonstrated to achieve a remarkable tumor-growth inhibition in comparison with chemotherapy or photothermal therapy alone. Results of immunohistochemical staining for caspase-3 and Ki-67 indicated the increased apoptosis and decreased proliferation of tumor cells contributed to the anti-tumor effect of chemo-photothermal treatment. In addition, DOX@PdPt@HA NPs induced negligible toxicity in vivo. Hence, the developed nanoplatform demonstrates great potential for applications in photothermal therapy, drug delivery and controlled release.

Designed construction of tween 60@2ß-CD self-assembly vesicles as drug delivery carrier for cancer chemotherapy.

We report a simple strategy to prepare Tween 60@2ß-CD self-assembly vesicles in aqueous solution as a new drug delivery carrier for cancer chemotherapy. The spherical shape of vesicles was confirmed by transmission electron microscopy (TEM) and mean particle sizes were about 33.7 nm, as measured by dynamic light scattering, micro-IR results indicated that the self-assembly vesicles was driven by hydrogen bonding. Hydrophilic doxorubicin (DOX) was successfully loaded into the self-assembly vesicles with drug loading content of 7.85% and loading efficiency of 42%. In addition, an in vitro cytotoxicity study and cellular uptake assays demonstrated that the DOX-loaded Tween 60@2ß-CD vesicles markedly enhanced the cellular uptake and cytotoxicity of DOX toward the Hela cells. Furthermore, when used to evaluate the in vivo therapeutic efficacy in mice bearing the breast cell line (4T1), DOX-loaded vesicles exhibited superior inhibition of tumor growth compared with the DOX solutions.

Engineering Gold Nanorod-Copper Sulfide Heterostructures with Enhanced Photothermal Conversion Efficiency and Photostability.

Plasmonic gold nanorods (Au NRs)-copper sulfide heterostructures have recently attracted much attention owing to the synergistically enhanced photothermal properties. However, the facile synthesis and interface tailoring of Au NRs-copper sulfide heterostructures remain a formidable challenge. In this study, the rational design and synthesis of Au NRs-Cu7 S4 heterostructures via a one-pot hydrothermal process is reported. Specifically, core-shell and dumbbell-like Au NRs-Cu7 S4 heterostructures are obtained with well-controlled interfaces by employing the Au NRs with different aspect ratios. Both core-shell and dumbbell-like Au NRs-Cu7 S4 have proven effective as photothermal therapy agents, which offer both high photothermal stability and significant photothermal conversion efficiency up to 62%. The finite-difference time domain simulation results confirm the coupling effect that leads to the enhanced local field as well as the optical absorption at the heterostructure interface. Importantly, these Au NRs-Cu7 S4 heterostructures can be compatibly used as an 808 nm laser-driven photothermal therapy agents for the efficient photothermal therapy of cancer cells in vitro. This study will provide new insight into the design of other noble metal-semiconductor heterostructures for a broad range of applications utilizing surface plasmon resonance enhancement phenomena.

One-Pot Synthesis of Noble Metal/Zinc Oxide Composites with Controllable Morphology and High Catalytic Performance.

The combination of noble metal and oxide support is a good approach to reduce the cost of noble metal catalyst and improve the stability of nanocatalyst in chemical reactions. Here, noble metal/zinc oxide composites, including Pd/ZnO and Pt/ZnO, have been facilely prepared through the general one-pot hydrothermal method. Importantly, the morphology of composites can be tuned from tube, flower, and star to skin needling-like shapes by easily adjusting the alkalinity of the reaction solution. By investigating the growth mechanism and influencing factors of the morphology of noble metal/zinc oxide composites, the differences of the morphology of composites can be ascribed to various growing units and directions of ZnO crystal under different alkalinities. Among them, Pd/ZnO composites exhibited both higher catalytic activity and excellent stability in the Suzuki coupling reaction between iodobenzene and phenylboronic acid and the reduction of 4-nitrophenol to 4-aminophenol by sodium borohydride. Such supported composites will potentially be used as green and sustainable catalysts for many chemical reactions.

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14.

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire(®) 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire(®) 44/14 (oil), 40% Solutol(®) HS 15 (surfactant), and 30% Transcutol(®) P (cosurfactant) (w/w) with 80 mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20 ± 1.43 and 33.34 ± 2.15 nm, and the melting points of them were 35.6 and 36.8 °C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of Cmax and AUC0-t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.

Facile synthesis of functionalized ionic surfactant templated mesoporous silica for incorporation of poorly water-soluble drug.

The present paper reported amino group functionalized anionic surfactant templated mesoporous silica (Amino-AMS) for loading and release of poorly water-soluble drug indomethacin (IMC) and carboxyl group functionalized cationic surfactant templated mesoporous silica (Carboxyl-CMS) for loading and release of poorly water-soluble drug famotidine (FMT). Herein, Amino-AMS and Carboxyl-CMS were facilely synthesized using co-condensation method through two types of silane coupling agent. Amino-AMS was spherical nanoparticles, and Carboxyl-CMS was well-formed spherical nanosphere with a thin layer presented at the edge. Drug loading capacity was obviously enhanced when using Amino-AMS and Carboxyl-CMS as drug carriers due to the stronger hydrogen bonding force formed between surface modified carrier and drug. Amino-AMS and Carboxyl-CMS had the ability to transform crystalline state of loaded drug from crystalline phase to amorphous phase. Therefore, IMC loaded Amino-AMS presented obviously faster release than IMC because amorphous phase of IMC favored its dissolution. The application of asymmetric membrane capsule delayed FMT release significantly, and Carboxyl-CMS favored sustained release of FMT due to its long mesoporous channels and strong interaction formed between its carboxyl group and amino group of FMT.

Biomimetic synthesized chiral mesoporous silica: Structures and controlled release functions as drug carrier.

This work initially illustrated the formation mechanism of chiral mesoporous silica (CMS) in a brand new insight named biomimetic synthesis. Three kinds of biomimetic synthesized CMS (B-CMS, including B-CMS1, B-CMS2 and B-CMS3) were prepared using different pH or stirring rate condition, and their characteristics were tested with transmission electron microscope and small angle X-ray diffraction. The model drug indomethacin was loaded into B-CMS and drug loading content was measured using ultraviolet spectroscopy. The result suggested that pH condition influenced energetics of self-assembly process, mainly packing energetics of the surfactant, while stirring rate was the more dominant factor to determine particle length. In application, indomethacin loading content was measured to be 35.3%, 34.8% and 35.1% for indomethacin loaded B-CMS1, indomethacin loaded B-CMS2 and indomethacin loaded B-CMS3. After loading indomethacin into B-CMS carriers, surface area, pore volume and pore diameter of B-CMS carriers were reduced. B-CMS converted crystalline state of indomethacin to amorphous state, leading to the improved indomethacin dissolution. B-CMS1 controlled drug release without burst-release, while B-CMS2 and B-CMS3 released indomethacin faster than B-CMS1, demonstrating that the particle length, the ordered lever of multiple helixes, the curvature degree of helical channels and pore diameter greatly contributed to the release behavior of indomethacin loaded B-CMS.

The effect of surface charge of glycerol monooleate-based nanoparticles on the round window membrane permeability and cochlear distribution.

The aim of this study is to elucidate the impact of surface charge of glycerol monooleate-based nanoparticles (NPs) on the cellular uptake and its distribution in the cochlea. These NPs are modified using varied concentration of anionic or cationic lipid. Upon dilution, these lipid mixtures self-assemble to form a series of cubic NPs with various surface charges, but with similar particle size. Positively charged NPs exhibited dose-dependent cytotoxicities against L929 cells proportional to the concentration of cationic lipid; whereas negatively charged NPs did not show obvious cytotoxic properties as compared to unmodified NPs. Meanwhile, confocal microscopy and flow cytometry results suggested that NPs with high positive surface charge were taken up more efficiently by L929 cells. The permeability of round window membrane (RWM) was high for highly positively charged NPs, which is likely due to their highly cellular uptake efficiency and consequently high concentration gradient between RWM and cochlear fluid. More importantly, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) modified NPs greatly facilitated broadly distribution in cochlea, favoring the treatment of hearing loss of low frequencies. Taken together, these findings about charge-dependent of NPs on RWM permeability and cochlear distribution could serve as guideline in the rational design of NP for drug and gene delivery to inner ear.

A general approach to mesoporous metal oxide microspheres loaded with noble metal nanoparticles.

Catalytic microspheres: A general approach is demonstrated for the facile preparation of mesoporous metal oxide microspheres loaded with noble metal nanoparticles (see TEM image in the picture). Among 18 oxide/noble metal catalysts, TiO(2)/0.1 mol % Pd microspheres showed the highest turnover frequency in NaBH(4) reduction of 4-nitrophenol (see picture).

Formation of different gold nanocrystal core-resin shell structures through the control of the core assembly and shell polymerization.

The formation of different Au nanocrystal core-resin shell structures through the control of the nanocrystal assembly and shell polymerization is investigated. 4-Mercaptophenol is employed together with formaldehyde as the resin monomers. 4-Mercaptophenol molecules bond to the surface of Au nanocrystals so that the resultant phenolic resin can intimately encapsulate Au nanocrystals. The morphologies of the obtained structures are determined by the nanocrystal assembly and the monomer polymerization behaviors, which are controlled by the solution pH as well as the monomer amounts. At pH = 8-9, Au nanorods are assembled and fused together under hydrothermal conditions in a preferential end-to-end manner. The fused structures are coated with a layer of resin, with the thickness controlled by the supplied amounts of the monomers. At pH = ∼10, Au nanorods are coated with resin of controllable thicknesses and separated from each other. The resin-coated Au nanorods are stable in both aqueous and nonaqueous solutions. At pH = ∼12, Au nanorods are coated with a thin layer of resin and assembled together in a side-by-side manner. A similar assembly and resin coating behavior is also observed with Au nanopolyhedrons. Moreover, plasmonic-fluorescent bifunctional structures are readily produced by incorporating CdTe nanocrystals in the resin shell that is coated on Au nanocrystals, owing to the presence of a number of thiol groups in the resin shell.

Plasmonic gold-superparamagnetic hematite heterostructures.

Bifunctional heterostructures composed of gold nanorods and hematite nanoparticle aggregates are prepared facilely through the hydrothermal decomposition of ferric acetylacetonate on the surface of the nanorods. The gold nanorod in the heterostructure is partially coated with the hematite nanoparticle aggregates. The hematite coating is porous. These heterostructures exhibit both plasmonic and superparamagnetic properties. They are well-dispersed in aqueous solutions. Such heterostructures will be potentially useful for many biotechnological applications.

Hydrothermal transformation from Au core-sulfide shell to Au nanoparticle-decorated sulfide hybrid nanostructures.

Core-shell Au nanorod-AgAuS nanostructures were hydrothermally prepared from Au nanorods and metal thiobenzoates and then transformed into Au nanoparticle-decorated sulfide nanostructures.

Syntheses, characterization, and photochromic studies of spirooxazine-containing 2,2'-bipyridine ligands and their zinc(II) thiolate complexes.

A series of photochromic spirooxazine-containing zinc(II) diimine bis-thiolate complexes were successfully synthesized, and their photophysical and photochromic properties were studied. The X-ray crystal structure of complex 1a has also been determined. Upon excitation by UV light at 330 nm, all the ligands and complexes exhibit photochromic behavior. The thermal bleaching kinetics of the ligands and the complexes were studied in dimethylformamide at various temperatures. The photochemical quantum yields for the photochromic reactions of the ligands and complexes were also determined.